Preparation method for novel benzylsulfinylpyridine compound

Abstract

The present invention relates to a preparation method for a novel benzylsulfinylpyridine compound, comprising using fluoropyridine, which contains electron-withdrawing substituents (such as halogen, trifluoromethyl, nitro, and cyano groups), as a starting material, and carrying out a substitution reaction and an oxidation reaction to obtain benzylsulfinylpyridine. According to the preparation method, a series of novel benzylsulfinylpyridine compounds can be obtained.

Description

Preparation method of new benzylsulfinyl pyridine compound TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry synthesis, and in particular, the present application relates to a new benzylsulfinyl pyridine compound and a preparation method thereof. BACKGROUND

[0002] The present application relates to a new benzylsulfinyl pyridine compound and a preparation method thereof, which is a white solid in appearance. The method has mild conditions, high reaction yield, and the purity of the product is more than 99%. The product can be further oxidized to generate sulfonic acid and sulfonyl chloride compounds, which are widely used in drug synthesis as an important molecular building block compound.

[0003] SUMMARY

[0004] The present application aims to provide a new benzylsulfinyl pyridine compound and a preparation method thereof. The method has low cost, simple process operation, high yield, and is suitable for industrial production. The synthesis method can better meet the requirements of high atomic economy, environmental friendliness, and operability in organic synthesis, and further meet the needs of industrial production and application.

[0005] The present application has the following configuration.

[0006] 1. A preparation method of a new benzylsulfinyl pyridine compound, characterized in that a fluoropyridine containing an electron-withdrawing substituent is used as a starting material, and a benzylsulfinyl pyridine is obtained through substitution reaction and oxidation reaction, comprising the following steps:

[0007] (A) Substitution reaction: reacting the fluoropyridine containing an electron-withdrawing substituent with benzyl mercaptan in the presence of an inorganic base to obtain a benzylthio pyridine;

[0008] (B) Oxidation reaction: mixing the above-mentioned benzylthio pyridine with NCS, stirring at room temperature under acidic conditions to complete the reaction, adjusting the pH of the system to precipitate the solid to obtain the benzylsulfinyl pyridine;

[0009] The chemical structural formula of the benzylsulfinyl pyridine is as follows:

[0010] Wherein, R1 is selected from halogen, trifluoromethyl, nitro, and cyano, and R2 is benzylsulfinyl.

[0011] 2. The preparation method of the benzylsulfinyl pyridine compound according to claim 1, characterized in that in step (A), the inorganic base is sodium carbonate or potassium carbonate.

[0012] 3. The method according to claim 1, wherein the reaction temperature in step (A) is 20-90 °C.

[0013] 4. The method according to claim 1, wherein the reaction time in step (A) is 2-10 h.

[0014] 5. The method according to claim 1, wherein the benzylsulfanylpyridine is obtained by cooling crystallization at a cooling temperature of 0-20 °C in step (A).

[0015] 6. The method according to claim 1, wherein the stirring time is 1-10 h in step (B).

[0016] 7. The method according to claim 1, wherein the pH is adjusted to 2-6 in step (B).

[0017] 8. The method according to claim 1, wherein the benzylsulfanylpyridine is obtained by stirring at room temperature with 5-15 V of purified water and suction filtration in step (B).

[0018] 9. The method according to claim 8, wherein the stirring time at room temperature with 5-15 V of purified water is 1-5 h.

[0019] Effects of the Invention

[0020] Compared with the prior art, the present application uses an electron-withdrawing substituted fluoropyridine as the starting material, which is inexpensive and easy to obtain, and the manufacturing method is simple and mild, does not require column chromatography, and can obtain high-purity benzylsulfanylpyridine through simple crystallization, thereby further saving time and cost. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is a mass spectrum of 3-(benzylsulfanyl)-5-chloropyridine synthesized in Example 1 - negative ion (MS)

[0022] Figure 2 is a nuclear magnetic resonance hydrogen spectrum of 3-(benzylsulfanyl)-5-chloropyridine synthesized in Example 1 (HNMR)

[0023] Figure 3 is a mass spectrum of 2-(benzylsulfanyl)-5-nitropyridine synthesized in Example 2 - positive ion (MS)

[0024] Figure 4 is a mass spectrum of 2-(benzylsulfinyl)-4-(trifluoromethyl)pyridine synthesized in Example 3 - positive ion (MS) DETAILED DESCRIPTION

[0025] The structural formula of the new benzylsulfinyl pyridine compound of the present application is as follows:

[0026] In the above structural formula, the substitution positions of the substituents R1 and R2 on the pyridine ring are not limited.

[0027] The present application provides a new synthesis route of the benzylsulfinyl pyridine compound as shown below:

[0028] In order to achieve the above-mentioned purpose, as one aspect of the present application, the present application adopts a technical scheme of obtaining benzylsulfinyl pyridine through substitution and oxidation from fluoropyridine containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and the like) as a starting material, which includes the following steps:

[0029] Step 1: substitution reaction of fluoropyridine containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and the like) with benzyl mercaptan under alkaline conditions to generate benzylsulfanyl pyridine through cooling, seeding and the like. The alkaline conditions can use inorganic bases such as sodium carbonate, potassium carbonate and the like; the cooling temperature is 0-20°C.

[0030] Step 2: oxidation reaction of benzylsulfanyl pyridine in the presence of NCS (N-chlorosuccinimide) after being dissolved with acid to generate benzylsulfinyl pyridine. The acid used in the reaction can use acidic solvents such as formic acid, acetic acid, oxalic acid and the like.

[0031] The new compound benzylsulfinyl pyridine obtained by the present application has multiple advantages in the reaction route: easy to obtain raw materials, mild reaction conditions, high chemical purity and the like.

[0032] Further, the technical scheme proposed by the present application preferably includes the following steps:

[0033] 1) reaction of fluoropyridine containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and the like) with benzyl mercaptan under alkaline conditions at 20-90°C for 2-10h, cooling, adding water and seed crystals for crystallization, and then suction filtration to obtain benzylsulfanyl pyridine.

[0034] 2) dissolving benzylsulfanyl pyridine in an acidic solvent, stirring at room temperature for 1-10h, adjusting the pH, beating with purified water, and then suction filtration to obtain benzylsulfinyl pyridine.

[0035] In the above manufacturing method, in order to further obtain the effect of mild reaction conditions and improve the yield, the following conditions are preferably adopted:

[0036] In the above substitution reaction of the present application, the reaction temperature and time can be appropriately set within the above range according to the target product. Preferably, the fluoropyridine containing an electron-withdrawing substituent (halogen, trifluoromethyl, nitro, cyano, etc.) is reacted with benzyl mercaptan under potassium carbonate basic conditions at 25°C to form benzylsulfanylpyridine, the reaction conditions are mild, the post-treatment is simple and convenient, and the yield can be further improved.

[0037] Preferably, the benzylsulfanylpyridine is dissolved in acetic acid, stirred at room temperature for 2h, and then the pH of the system is adjusted to 3 to obtain benzylsulfinylpyridine. The reaction conditions are mild, and the yield and purity can be further improved.

[0038] As another aspect of the present application, in the oxidation reaction of the present application, the selection of the oxidizing agent is extremely important because the oxidation reaction is difficult to perform. Commonly used oxidizing agents include hydrogen peroxide, peroxy acid, periodic acid and its salts, nitrogen-containing compounds such as nitric acid, halogens, and electrophilic halides, etc. However, m-chloroperoxybenzoic acid (mCPBA) is expensive and not suitable for large-scale industrial production; peroxy acids such as peroxyacetic acid and hydrogen peroxide are extremely dangerous and difficult to use in large quantities because they are explosive; periodic acid and its salts are strong oxidizing agents, expensive, and not suitable for large-scale industrial production, and their wastewater can easily pollute water bodies and soil, harming the water ecosystem and the normal growth of crops; halogens such as chlorine and bromine are not easy to store and have high toxicity, and are not suitable for large-scale industrial production.

[0039] In the present application, NCS is used as an oxidizing agent. Compared with other oxidizing agents, NCS has stable chemical properties, is relatively safe, has good tolerance to various functional groups in the substrate, is widely available in the market, and is inexpensive. Therefore, it is more beneficial to obtain the target product under mild conditions with a high yield. The oxidation mechanism of NCS is speculated as follows: first, the S atom of the intermediate benzyl sulfide attacks the N-Cl bond of NCS to generate a sulfonium ion, then the electrophilic sulfonium ion is attacked by the acetate in the reaction system to generate an intermediate containing a S-O bond (sulfur ylide), this intermediate further forms a sulfur-oxygen tetra-ring intermediate state, and finally forms a benzyl sulfinyl compound and a byproduct acetaldehyde. Compared with strong oxidizing agents such as peroxy acid, NCS used in the present application can obtain higher selectivity, and thus is beneficial to improve the yield.

[0040] Further, by adjusting the pH, the benzylsulfinylpyridine can be maintained in an ionic state, which is further beneficial to precipitate it to obtain it with a high yield and purity.

[0041] The synthesis method of the new benzylsulfinyl pyridine compound according to the application is environment-friendly, operable, and can meet the demand of industrial production application. The series of compounds can be further oxidized to generate sulfonic acid, the sulfonic acid is a water-soluble strong acid compound, can be substituted by halogen atoms, amino groups and the like, and provides a wider clinical candidate for the field of molecular building blocks and new drug research and development. Therefore, the compound has great utilization value in industry.

[0042] Embodiments of the application are described in detail below, it should be noted that the embodiments described below are exemplary and are only used to explain the application, and cannot be understood as a limitation of the application. In addition, if not specifically stated, all reagents used in the following examples are commercially available or can be synthesized according to the methods described herein or known methods, and the reaction conditions not listed are also known and easily obtained by those skilled in the art.

[0043] Example 1

[0044] Preparation of a new compound 3-(benzylsulfinyl)-5-chloropyridine

[0045] The specific synthesis method of a new compound 3-(benzylsulfinyl)-5-chloropyridine is as follows:

[0046] Preparation of 3-(benzylsulfinyl)-5-chloropyridine

[0047] In a dry reaction bottle, 3-chloro-5-fluoropyridine (5.0 g, 38 mmol), anhydrous potassium carbonate (6.3 g, 45.6 mmol), 50 ml of DMF, benzyl mercaptan (4.7 g, 38 mmol) were added, and after nitrogen protection, 60°C heating and stirring for 5h, TLC (PE:EA=10:1) was used to monitor the disappearance of raw materials, and the heating was stopped. The reaction system was cooled to room temperature, then 150 ml of purified water was added, cooled to 5-15°C, then 10 mg of crystal seeds were added, and solid was precipitated, the temperature was controlled at 5-15°C, stirred for 1h, filtered, the filter cake was washed with 100 ml of purified water, and vacuum drying at room temperature was used to obtain 8.5 g of white solid, the yield was 94.9%, and the purity was more than 98%.

[0048] Preparation of 3-(benzylsulfinyl)-5-chloropyridine

[0049] Into a dry and clean 100ml reaction flask, 3-(benzylsulfanyl)-5-chloropyridine (7.9g, 33.5mmol), NCS (4.9g, 36.9mmol), 32ml glacial acetic acid, 11ml purified water, after nitrogen protection, stirring at room temperature for 1h, TLC (PE:EA=10:1) monitoring raw material disappearance, the reaction system using saturated sodium bicarbonate aqueous solution to adjust the system pH to 4, white solid precipitated, then add 80ml purified water, stirring at room temperature for 1h, filtration, filter cake using 100ml purified water, after drying to get 7.6g white solid, yield 90%, purity more than 99%.

[0050] Example 2

[0051] Preparation of a new compound 2-(benzylsulfinyl)-5-nitropyridine

[0052] Preparation of 2-(benzylsulfanyl)-5-nitropyridine

[0053] Into a dry reaction flask, 2-fluoro-5-nitropyridine (14.2g, 100mmol), anhydrous potassium carbonate (18.0g, 130mmol), 80ml DMF, benzyl mercaptan (13.0g, 105mmol), after nitrogen protection, stirring at 20-30℃ for 2h, TLC (PE:EA=19:1) monitoring raw material disappearance, post-processing. The reaction system was cooled to 0-10℃, then 250ml purified water was added, a large amount of solid was precipitated, stirring at 0-20℃ for 2h, filtration, filter cake using 100ml purified water, 45℃ air drying to get 22.5g light yellow solid, yield 91.4%, liquid phase purity more than 98%.

[0054] Preparation of 2-(benzylsulfinyl)-5-nitropyridine

[0055] Into a dry and clean 100ml reaction flask, 3-(benzylsulfanyl)-5-chloropyridine (7.9g, 33.5mmol), NCS (4.9g, 36.9mmol), 32ml glacial acetic acid, 11ml purified water, after nitrogen protection, stirring at room temperature for 1h, TLC (PE:EA=10:1) monitoring raw material disappearance, the reaction system using saturated sodium bicarbonate aqueous solution to adjust the system pH to 4, white solid precipitated, then add 80ml purified water, stirring at room temperature for 1h, filtration, filter cake using 100ml purified water, after drying to get 7.6g white solid, yield 90%, purity more than 99%.

[0056] Example 3

[0057] Preparation of a novel compound 2-(benzylsulfinyl)-4-(trifluoromethyl)pyridine

[0058] Preparation of 2-(benzylthio)-4-(trifluoromethyl)pyridine

[0059] Into a dry reaction flask, 2-fluoro-4-(trifluoromethyl)pyridine (16.5 g, 100 mmol), anhydrous potassium carbonate (18.0 g, 130 mmol), 85 ml DMF, benzyl mercaptan (13.7 g, 110 mmol) were added. After nitrogen protection, the mixture was stirred at 20-30 °C for 2 h. The disappearance of the starting material peak was monitored by liquid chromatography. The reaction system was cooled to 0-15 °C, then 350 ml purified water was added. A large amount of solid was precipitated. The temperature was controlled at 0-20 °C and stirred for 2 h. Filtration was performed. The filter cake was rinsed with 50 ml purified water. The product was dried at 45 °C with air blowing to obtain 24 g of 2-(benzylthio)-4-(trifluoromethyl)pyridine as a light yellow solid with a yield of 89.1% and a liquid chromatography purity of more than 98%.

[0060] Preparation of 2-(benzylsulfinyl)-4-(trifluoromethyl)pyridine

[0061] Into a dry and clean reaction flask, 2-(benzylthio)-4-(trifluoromethyl)pyridine (20.0 g, 81.2 mmol), NCS (11.9 g, 89.3 mmol), 100 ml glacial acetic acid, 20 ml purified water were added. After nitrogen protection, the mixture was stirred at room temperature for 2 h. TLC (PE:EA = 19:1) was used to monitor the disappearance of the starting material. The reaction system was adjusted to pH 4 with saturated sodium bicarbonate aqueous solution. White solid was precipitated. Then 800 ml purified water was added. The mixture was stirred at room temperature for 2 h. Filtration was performed. The filter cake was rinsed with 20 ml purified water. After drying, 20 g of 2-(benzylsulfinyl)-4-(trifluoromethyl)pyridine was obtained as a white solid with a yield of 94.3% and a purity of more than 99%.

[0062] Example 4

[0063] Preparation of a novel compound 5-(benzylsulfinyl)-2-cyanopyridine

[0064] Preparation of 5-(benzylthio)-2-cyanopyridine

[0065] Into a dry reaction flask, 2-cyano-5-fluoropyridine (12.2 g, 100 mmol), anhydrous potassium carbonate (18.0 g, 130 mmol), 75 mL of DMF, benzyl mercaptan (13.7 g, 110 mmol) were added. After nitrogen protection, the mixture was stirred at 70-80 °C for 3 h. The reaction was monitored by liquid chromatography. After the starting material peak disappeared, the reaction was cooled to 0-15 °C and then 300 mL of purified water was added. A large amount of solid was precipitated. The mixture was stirred at 0-20 °C for 3 h. The solid was filtered and the filter cake was washed with 50 mL of purified water. The solid was dried at 45 °C to give 20 g of 5-(benzylsulfanyl)-2-cyanopyridine as a light yellow solid with a yield of 88.4% and a liquid chromatography purity of more than 98%.

[0066] Preparation of 5-(benzylsulfinyl)-2-cyanopyridine

[0067] Into a dry and clean reaction flask, 5-(benzylsulfanyl)-2-cyanopyridine (11.3 g, 49.9 mmol), NCS (7.3 g, 54.9 mmol), 50 mL of glacial acetic acid, 10 mL of purified water were added. After nitrogen protection, the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (PE:EA = 15:1). After the starting material disappeared, the reaction was adjusted to pH 4 with saturated sodium bicarbonate aqueous solution. White solid was precipitated. Then 300 mL of purified water was added. The mixture was stirred at room temperature for 2 h. The solid was filtered and the filter cake was washed with 20 mL of purified water. After drying, 11.2 g of 5-(benzylsulfinyl)-2-cyanopyridine was obtained as a white solid with a yield of 92.6% and a purity of more than 99%.

[0068] Comparative Example 1

[0069] In Example 1, instead of adjusting the pH of the system to precipitate the product, the reaction was extracted with 300 mL of ethyl acetate three times. The organic phase was washed with saturated brine until it was neutral. Then, the organic phase was dried with anhydrous sodium sulfate and concentrated to give the product. The yield was 100% and the purity was 85%.

[0070] In summary, the above description of the specific embodiments of the present application does not limit the present application. Those skilled in the art can make changes or modifications to the present application according to the present application, as long as they do not deviate from the spirit of the present application, which should belong to the scope of the appended claims of the present application.

Claims

1. A novel method for preparing benzylsulfinylpyridine compounds, characterized in that, The benzylsulfinyl pyridine is obtained from fluoropyridine containing electron-withdrawing substituent as starting material through substitution reaction and oxidation reaction, including the following steps: (A) Substitution reaction: fluoropyridine containing electron-withdrawing substituent is reacted with benzyl mercaptan in the presence of inorganic base to obtain benzylthio pyridine; (B) Oxidation reaction: the above benzylthio pyridine is mixed with NCS, and then stirred at room temperature under acidic condition until the reaction is completed, then the pH of the system is adjusted to precipitate solid to obtain benzylsulfinyl pyridine; The chemical structural formula of the benzylsulfinylpyridine is as follows: Wherein, R1 is one selected from halogen, trifluoromethyl, nitro, cyano, and R2 is benzylsulfinyl.

2. The method for preparing benzylsulfinylpyridine compounds as described in claim 1, characterized in that, In step (A), the inorganic base is sodium carbonate or potassium carbonate.

3. The method for preparing benzylsulfinylpyridine compounds as described in claim 1, characterized in that, The reaction temperature in step (A) is 20-90℃.

4. The method for preparing benzylsulfinylpyridine compounds as described in claim 1, characterized in that, The reaction time in step (A) is 2-10h.

5. The method for preparing benzylsulfinylpyridine compounds as described in claim 1, characterized in that, In step (A), the benzylthio pyridine is obtained by crystallization through temperature reduction under the condition that the temperature reduction temperature is 0-20℃.

6. The method for preparing benzylsulfinylpyridine compounds as described in claim 1, characterized in that, In step (B), the stirring time during the reaction is 1-10h.

7. The method for preparing benzylsulfinylpyridine compounds as described in claim 1, characterized in that, In step (B), the pH is adjusted to 2-6.

8. The method for preparing benzylsulfinylpyridine compounds as described in claim 1, characterized in that, In step (B), 5V-15V purified water is added for room temperature stirring, and suction filtration is performed to obtain benzylsulfinyl pyridine.

9. The method for preparing benzylsulfinylpyridine compounds as described in claim 8, characterized in that, The time for room temperature stirring by adding 5V-15V purified water is 1-5h.

Images